Cancer is a complex disease with a range of genetic, genomic, and environmental factors that can impact disease development, progression, and response to therapy. These factors exhibit broad heterogeneity: large variations are seen between individuals in germline DNA sequence, tumor genetics, or histological subtypes, and environmental exposures. A high level of complexity is seen in the patterns of inherited genetic variants (SNPs) in the normal host DNA, and in the combinations of somatic genetic events and gene expression changes in tumors. In addition, complex interactions exist between the genetics of the host and environmental exposures that contribute to tumor susceptibility. The overall goal of the Cancer Genetics Program (Program) is to elucidate the genetics of tumor susceptibility, tumorigenesis, and progression; and to use this information clinically to improve cancer management. The central themes of the Program that we aim to further develop in the next five years are: (1) Genetics of Cancer Susceptibility, Progression, and Response; (2) Cancer Genome and Epigenome; (S) Functional Genomics; and (4) Systems Genetics of Cancer. The Program brings together experts in the application of advanced genomic and genetic analysis tools to identify abnormalities that contribute to cancer genesis and progression by utilizing the outstanding mouse and human genetic resources at UCSF. There are 24 members in the Program, and they represent 12 Departments from the Schools of Medicine and Pharmacy at UCSF. The NCI and other peer-reviewed support among Program members during the last budget year was $13,592,313, in total. Since 2007, 492 total papers were published by members of the Program, with 12 percent intra- and 33 percent interprogrammatic. Program members are fully integrated into the organ site-specific programs, and participate broadly in seminars, and discussion groups organized by the Program; and in conjunction with other research programs (e.g., the Cancer Genetics Risk Program, and the Human Genetics Program). Ultimately the Program aims to encourage and support cross-cutting research that encompasses both germline and somatic approaches to deciphering the genetic basis of cancer.